Journal article Closed Access

Efficient tritiation of the translocator protein (18kDa) selective ligand DPA-714

Damont, Annelaure; Garcia-Argote, Sébastien; Buisson, David-Alexandre; Rousseau, Bernard; Dollé, Frédéric


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    <subfield code="a">&lt;p&gt;DPA-714 (N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide) is a recently&amp;nbsp;discovered fluorinated ligand of the translocator protein 18 kDa (TSPO). Labelled with the short-lived positron emitter&amp;nbsp;fluorine-18, this structure is today the radioligand of reference for in vivo imaging of microglia activation and&amp;nbsp;neuroinflammatory processes with positron emission tomography. In the present work, an isotopically tritium-labelled&amp;nbsp;version was developed ([3H]DPA-714), in order to access high resolution in vitro and ex vivo microscopic autoradiography&amp;nbsp;studies, repeated and long-lasting receptor binding studies and in vivo pharmacokinetic determination at late time points.&amp;nbsp;Briefly, DPA-714 as reference, and its 3,5-dibrominated derivative as precursor for labelling, were both prepared from DPA-713 in nonoptimized 32% (two steps) and 10% (three steps) yields, respectively. Reductive debromination using deuterium&amp;nbsp;gas and Pd/C as catalyst in methanol, performed at the micromolar scale, confirmed the regioselective introduction of two&amp;nbsp;deuterium atoms at the meta positions of the phenyl ring. Tritiodebromination was analogously performed using no-carrier&amp;nbsp;tritium gas. HPLC purification provided &amp;gt;96% radiochemically pure [3H]DPA-714 (7 GBq) with a 2.1 TBq/mmol specific&amp;nbsp;radioactivity. Interestingly, additional hydrogen-for-tritium exchanges were also observed at the 5-methyl and 7-methyl&amp;nbsp;positions of the pyrazolo[1,5-a]pyrimidine, opening novel perspectives in the labelling of compounds featuring this&amp;nbsp;heterocyclic core.&lt;/p&gt;</subfield>
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    <subfield code="u">CEA, DSV/I2BM, Service Hospitalier Frédéric Joliot, 91401 Orsay, France</subfield>
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    <subfield code="a">Efficient tritiation of the translocator protein (18kDa) selective ligand DPA-714</subfield>
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